Differentiation of tumour-stage mycosis fungoides, psoriasis vulgaris and normal controls in a pilot study using serum proteomic analysis

BACKGROUND: Serum proteomic analysis is an analytical technique utilizing high-throughput mass spectrometry (MS) in order to assay thousands of serum proteins simultaneously. The resultant 'proteomic signature' has been used to differentiate benign and malignant diseases, enable disease prognosis, and monitor response to therapy. OBJECTIVES: This pilot study was designed to determine if serum protein patterns could be used to distinguish patients with tumour-stage mycosis fungoides (MF) from patients with a benign inflammatory skin condition (psoriasis) and/or subjects with healthy skin. METHODS: Serum was analysed from 45 patients with tumour-stage MF, 56 patients with psoriasis, and 47 controls using two MS platforms of differing resolution. An artificial intelligence-based classification model was constructed to predict the presence of the disease state based on the serum proteomic signature. RESULTS: Based on data from an independent testing set (14-16 subjects in each group), MF was distinguished from psoriasis with 78.6% (or 78.6%) sensitivity and 86.7% (or 93.8%) specificity, while sera from patients with psoriasis were distinguished from those of nonaffected controls with 86.7% (or 93.8%) sensitivity and 75.0% (or 76.9%) specificity (depending on the MS platform used). MF was distinguished from unaffected controls with 61.5% (or 71.4%) sensitivity and 91.7% (or 92.9%) specificity. In addition, a secondary survival analysis using 11 MS peaks identified significant survival differences between two MF groups (all P-values <0.05). CONCLUSIONS: Serum proteomics should be further investigated for its potential to identify patients with neoplastic skin disease and its ability to determine disease prognosis.     

Topical carmustine (BCNU) in the treatment of mycosis fungoides

The University of California, San Francisco (UCSF), experience with topical carmustine (BCNU) in the treatment of approximately 200 patients with mycosis fungoides (MF) is summarized. Topical BCNU is an effective treatment for patch- and early plaque-stage MF. Side-effects are usually not a major deterrent to continuation of therapy.     

Profiles of Foxp3+ regulatory T cells in eczematous dermatitis, psoriasis vulgaris and mycosis fungoides

Background It is well known that regulatory T cells (Tregs), identified by their expression of CD4, CD25 and Foxp3, play a crucial role in maintaining peripheral tolerance. Recently, it has been demonstrated that a Treg population resides in normal human skin. However, only a few studies have demonstrated the presence of Foxp3+ Tregs in inflammatory skin disorders. Objectives In this study, we immunohistologically examined the presence of CD4+ CD25+ Foxp3+ Tregs in the lesional skin of psoriasis vulgaris, mycosis fungoides and eczematous dermatitis. Methods We used immunohistochemistry to examine the presence of Foxp3+ Tregs in fixed sections of the lesional skin from 16 patients with psoriasis vulgaris, 17 patients with mycosis fungides and 18 patients with eczematous dermatitis in addition to 10 normal skin samples. Results In normal skin, epidermal and dermal Foxp3+ cells were rare. The psoriasis vulgaris, mycosis fungoides and eczematous dermatitis samples contained substantial numbers of epidermal and dermal CD3+, CD4+ and CD25+ Foxp3+ Tregs. The epidermis contained a higher percentage of CD3+, CD4+ and CD25+ Foxp3+ cells than the dermis. The percentage of Foxp3+ cells among CD3+ or CD4+ cells was significantly lower in eczematous dermatitis than in psoriasis vulgaris or mycosis fungoides, and that of dermal Foxp3+ cells was significantly lower in psoriasis vulgaris than in eczematous dermatitis or mycosis fungoides. Conclusions The lower percentage of epidermal or dermal Foxp3+ cells in eczematous dermatitis or psoriasis vulgaris, respectively, might contribute to their pathogenesis.     

Etoposide as a single agent in the treatment of mycosis fungoides: A retrospective analysis

Several chemotherapy agents have shown efficacy in the treatment of mycosis fungoides (MF). In the literature, there is limited data on the use of single agent etoposide for MF. We aimed to retrospectively review our experience with single agent etoposide in the treatment of advanced‐stage or refractory early‐stage MF with focus on analyzing its efficacy and safety. We included 13 MF patients who were treated with single agent etoposide. Patients were identified through the Cutaneous T Cell Lymphoma Database of Indiana University that involves patients treated from 2006 to 2016. Overall nine patients (69%) responded to treatment. No complete response was identified. Median time to response was 12.5 weeks (range: 6–25.4). Median duration of response was 43 weeks (range: 5–60) and median time to treatment failure was 31.3 weeks (range: 12.4–230). Hematological toxicity was observed in eight patients including two patients with grade 4 neutropenia and/or lymphopenia leading to sepsis. Higher doses of etoposide were significantly correlated with higher grades of anemia, neutropenia or lymphopenia (p < .05). Our study demonstrates that etoposide is an effective treatment for MF and may be considered in selected patients with progressive MF who have failed other treatments.     

Efficacy of monochromatic excimer laser radiation (308 nm) in the treatment of early stage mycosis fungoides

BACKGROUND: Various reports have recently shown the efficacy of narrowband ultraviolet (UV) B phototherapy at 311 nm in the treatment of early stage mycosis fungoides (MF). OBJECTIVES: To examine the effectiveness and tolerability of monochromatic excimer light (MEL) at 308 nm as a first treatment for early stage MF (stage IA). METHODS: Ten lesions from five patients with a clinical and histological diagnosis of MF were treated with repeated applications of MEL until complete remission was achieved or up to a maximum of 10 applications, with a cumulative dose of 308 nm UVB of between 6 and 12 J cm(-2). All patients were observed every 2 weeks for 2 months, with a 1-year follow-up. Results At present, all patients are in complete remission, with no side-effects. CONCLUSIONS: Based on these results, MEL can be considered a useful tool in the treatment of early stage MF.     

Juvenile mycosis fungoides with large‐cell transformation: Successful treatment with psoralen with ultraviolet A light,interferon‐alfa,and localized radiation

Mycosis fungoides with large‐cell transformation is historically associated with a poor prognosis. Pediatric cases of mycosis fungoides with large‐cell transformation are rare, with only three other cases reported in the literature. We present the first case of a child with almost complete remission of his mycosis fungoides with large‐cell transformation shortly after administration of psoralen plus ultraviolet A, interferon‐alfa, and localized radiation.     

Folliculotropic mycosis fungoides: Clinical characteristics,treatments, and long‐term outcomes of 53 patients in a tertiary hospital

Folliculotropic mycosis fungoides (FMF) is characterized by a broad clinical spectrum and worse prognosis compared to classical MF. This study aimed to evaluate the clinical characteristics, treatment modalities and long‐term outcome and risk factors for progression and survival of FMF patients. We conducted a single‐center retrospective study and reviewed 53 patients diagnosed with FMF between 1990 to 2019 in a referral center at Ankara University, Turkey. Regarding to stage at diagnosis, 24 patients (45.3%) had advanced‐stage disease (≥IIB). Follicular papules was observed in 66% and alopecia in 49.1% of the cases. Forty‐three patients (81.1%) suffered from pruritus. The majority of the patients (92.4%) had at least one systemic therapy. Complete remission was achieved in 24.5% of the patients. The median time of overall survival (OS) was 50 months (range 9‐324 months) and 5‐year and 10‐year OS was 83% and 69%, respectively. Twenty‐eight (52.3%) patients progressed to more advanced stages and seven (13.2%) patients died due to MF during the follow‐up period. FMF is associated with a progressive course and in most patients, skin‐directed therapies were found to be inefficient to control the disease and multiple systemic therapeutic agents were required to control the disease.     

Narrow band UVB (311 nm), psoralen UVB (311 nm) and PUVA therapy in the treatment of early-stage mycosis fungoides: a right-left comparative study

BACKGROUND: Psoralen ultraviolet A (PUVA) is a widely used first-line therapy for treatment of early cutaneous T-cell lymphoma. Narrow band UVB (UVB-NB) (311 nm) has been recently introduced as another effective line of treatment. It is postulated that the efficacy of UVB-NB could be enhanced by addition of psoralen. AIM: The aim of the present work was to compare the clinical and histopathologic efficacy of PUVA and UVB-NB in the treatment of early-stage MF (stages IA, IB and IIA), and to evaluate whether psoralen adds to the efficacy of UVB-NB or not. Patients and Methods: Twenty patients (stage IA, IB or IIA) were divided into two equal groups: group I received UVB-NB on the right body half vs. PUVA on the left side of the body for 48 sessions, and group II received PUVB-NB on the right side of the body vs. PUVA on the left side for 36 sessions. The sessions were administered three times weekly. RESULTS: In group I, almost equal results were obtained on both sides, i.e., UVB-NB and PUVA were equally effective in the treatment of early stages of MF, both clinically and histopathologically. In group II, PUVB-NB was found to be as effective as conventional PUVA in the treatment of early-stage mycosis fungoides, also on both clinical and histopathological grounds. CONCLUSION: UVB-NB phototherapy should be included among the initial therapeutic options of mycosis fungoides in view of its efficacy, convenience, and likelihood of fewer long-term adverse effects. Addition of psoralen does not seem to enhance its therapeutic efficacy.     

Comparison of the efficacy of local narrowband ultraviolet B (NB-UVB) phototherapy versus psoralen plus ultraviolet A (PUVA) paint for palmoplantar psoriasis

Palmoplantar psoriasis is an idiopathic disabling condition, often resistant to conventional therapies. The purpose of this study was to evaluate the efficacy and safety of local narrowband ultraviolet B (NB-UVB) phototherapy and to compare it with local psoralen plus ultraviolet A (PUVA) paint in patients with palmoplantar psoriasis unresponsive to conventional therapies other than phototherapy. A cohort of 25 patients with palmoplantar psoriasis were included in this study, which was based on a left-to-right comparison pattern. The treatments were administered with local narrowband UVB irradiation on one side and local PUVA on the other side three times a week over 9 weeks. Clinical assessments were performed at baseline and every 3 weeks during the 9-week treatment. There was a statistically significant decrease in the mean clinical scores at the third, sixth and ninth week with both treatments. The difference in clinical response between the two treatment modalities was statistically significant at the end of the treatment period, with the percentage reduction in severity index scores with the PUVA-paint-treated side being 85.45% compared with 61.08% for the NB-UVB treated side (t = 5.379, P = 0.0001, Student's t-test for unpaired samples). Our results show that, although some clinical improvement was achieved with local NB-UVB phototherapy, the results were better with local PUVA, and such a treatment option may be reserved for patients with palmoplantar psoriasis who experience phototoxic reaction to psoralens.     

Psoralen plus ultraviolet A +/- interferon-alpha treatment resistance in mycosis fungoides: the role of tumour microenvironment, nuclear transcription factor-kappaB and T-cell receptor pathways

Background  Interferon (IFN)-α is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA ± IFN-α treatment.
Objectives  To identify factors responsible for resistance to PUVA ± IFN-α treatment in MF patients.
Patients/methods  The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-α clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment.
Results  Genes involved in NF-κB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma.
Conclusions  Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-κB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment.     

Evaluation of the effect of narrow band‐ultraviolet B on the expression of tyrosinase,TYRP‐1, and TYRP‐2 mRNA in vitiligo skin and their correlations with clinical improvement: A retrospective study

Narrowband‐ultraviolet B (NB‐UVB) is considered one of the main therapeutic tools in vitiligo, which is able to induce repigmentation and halt depigmentation. However, little remains known about the effect of NB‐UVB on TYR gene family, the main pigmentary genes, in vitiligo patients. To assess the effect of NB‐UVB on expression of some genes related to the pigmentary problem of vitiligo; tyrosinase (TYR), tyrosinase related protein 1 (TYRP1) and tyrosinase related protein 2 (TYRP2), mRNA levels of those genes were quantitatively evaluated by Real‐Time quantitative Polymerase Chain Reaction (RT‐qPCR) in skin biopsies obtained from 30 patients with nonsegmental vitiligo and five healthy controls. Vitiligo patients were classified into two groups; group 1, involving 12 untreated vitiligo patients and group 2, including 18 vitiligo patients treated by NB‐UVB. The levels of TYR, TYRP‐1, and TYRP‐2 mRNAs in untreated group were significantly lower than in control subjects (P < .001). In NB‐UVB treated group, the three genes were significantly higher than in group 1 (P < .001), however, they were still significantly lower than in the control subjects (P < .001). A significant positive correlation was detected between TYR and TYRP‐2 genes in group 2 (P = .03). This study demonstrated that mRNA level of TYR, TYRP‐1, and TYRP‐2, which decreased in vitiligo, was significantly increased upon treatment with NB‐UVB. Accordingly, the mechanism of depigmentation in vitiligo disease and repigmentation by NB‐UVB treatment may be related to the changes in the expression of these genes.     

Safety and efficacy of a fixed-dose cyclosporin microemulsion (100 mg) for the treatment of psoriasis

Cyclosporin is a second-line modality for the treatment of psoriasis. The long-term efficacy of cyclosporin and potential adverse side-effects, however, are a concern to patients. Therefore, a cyclosporin microemulsion (Neoral), which is steadily absorbed at an ultra-low dosage (1-2 mg/kg per day) or low dosage (2-3 mg/kg per day), is currently recommended. The dose must be calculated based on patient bodyweight and the blood concentration monitored regularly, which is time-consuming. Furthermore, the concentration is related to the safety profile, but not to efficacy. We examined whether a fixed-dose cyclosporin microemulsion (100 mg/day) is effective for treating psoriasis. Enrolled patients (n = 40) were given either 100 mg cyclosporin emulsion once daily (group A) or 50 mg twice daily (group B), regardless of patient weight and condition, before meals in a randomized controlled study. Patient bodyweight ranged 50-80 kg. We assessed the serum cyclosporin concentration 1 h after administrating the medicine (C1 score), Psoriasis Area and Severity Index (PASI) score, quality of life, and the results of regular blood examinations. The improvement rate was 69.4 ± 4.8% in group A and 73.4 ± 4.3% in group B. PASI-50 was achieved by 82% in group A and 84% in group B. At 6 weeks, the number of patients with PASI-50 was significantly higher in group A than in group B. PASI-75 and -90 were also achieved in both groups with no significant difference between groups. Administration of a fixed-dose cyclosporin microemulsion (100 mg/day) is practical for second-line psoriasis treatment.